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Abstract

Objectives

Clopidogrel is effective at decreasing cardiovascular events in patients with peripheral artery disease (PAD); however, its effect on limb outcomes are less known. This study investigated the variability in response to clopidogrel and its relationship with clinical limb outcomes.

Methods

Three hundred subjects were enrolled in the Platelet Activity and Cardiovascular Events (PACE) study prior to lower extremity revascularization, of whom 104 were on clopidogrel. Light transmission platelet aggregation was measured in response to ADP 2 $μ$ m immediately prior to revascularization. Patients were followed longitudinally for a median follow-up of 18 months. The primary endpoint was major adverse limb events (MALE) defined by major amputation or reoperation of the affected limb. Patients were stratified into groups according to percent ADP-induced aggregation. Poor response to clopidogrel was defined by >50% aggregation.

Results

Overall, the median age was 70 (63, 76) and 35.6% were female. Twenty-nine (27.9%) patients experienced MALE during their follow-up. Median aggregation to ADP 2 $μ$ m was 22.5% (Q1-Q3: 10%, 50%) and 27 subjects (26%) were clopidogrel poor responders. Baseline aggregation was higher in subjects who went on to develop a MALE than those without MALE (43% vs 20%, p = .017). Subjects with aggregation > median (22.5%) were more likely to experience MALE than aggregation < median (38.5% vs 17.3%, p = .029). After multivariable adjustment for age, sex, race/ethnicity, BMI, diabetes, coronary artery disease, and aspirin use, aggregation > median was associated with MALE (adjusted HR [aHR] 2.67, 95% CI 1.18–6.01, p = .018). When stratified by established cut-offs for responsiveness to clopidogrel (50% aggregation), poor responders were more likely to experience MALE than normal responders (44.4% vs 22.1%, aHR 2.18, 95% CI 1.00–4.78, p = .051).

Conclusions

Among patients undergoing lower extremity revascularization on clopidogrel, higher baseline percent aggregation is associated with increased risk for major adverse limb events.

Keywords

peripheral artery disease revascularization clopidogrel platelets

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References

Fowkes

Rudan

, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013; 382(9901): 1329–1340. DOI: 10.1016/S0140-6736(13)61249-0

Ouriel

. Peripheral arterial disease. Lancet 2001; 358(9289): 1257–1264. DOI: 10.1016/S0140-6736(01)06351-6

Dann

Hadi

Montenont

, et al. Platelet-derived MRP-14 induces monocyte activation in patients with symptomatic peripheral artery disease. J Am Coll Cardiol 2018; 71(1): 53–65. DOI: 10.1016/j.jacc.2017.10.072

Brandt

Iturria

, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5(12): 2429–2436. DOI: 10.1111/j.1538-7836.2007.02775.x

Corliss

Freedman

Brennan

, et al. Laboratory assessments of therapeutic platelet inhibition in endovascular neurosurgery: complication prediction using the VerifyNow P2Y12 assay and thromboelastography with platelet mapping. J Neurosurg 2020; 134(3):884–892. DOI: 10.3171/2019.12.JNS192396

Sangkuhl

Klein

Altman

. Clopidogrel pathway. Pharmacogenet Genomics 2010; 20(7): 463–465. DOI: 10.1097/FPC.0b013e3283385420

Dorsam

Kunapuli

. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004; 113(3): 340–345. DOI: 10.1172/JCI20986

Berenson

Hawken

Fort

, et al. Clopidogrel resistance is common in patients undergoing vascular and coronary interventions. Vascular 2022; 17085381211059394. DOI: 10.1177/17085381211059394

Damman

Woudstra

Kuijt

, et al. P2Y12 platelet inhibition in clinical practice. J Thromb Thrombolysis 2012; 33(2): 143–153. DOI: 10.1007/s11239-011-0667-5

10.

Jiang

Samant

Lesko

, et al. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet 2015; 54(2): 147–166. DOI: 10.1007/s40262-014-0230-6

11.

Patrono

Bachmann

Baigent

, et al. Expert consensus document on the use of antiplatelet agents. the task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology. Eur Heart J 2004; 25(2): 166–181. DOI: 10.1016/j.ehj.2003.10.013

12.

Nguyen

Diodati

Pharand

. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005; 45(8): 1157–1164. DOI: 10.1016/j.jacc.2005.01.034

13.

Matetzky

Shenkman

Guetta

, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109(25): 3171–3175. DOI: 10.1161/01.CIR.0000130846.46168.03

14.

Guirgis

Thompson

Jansen

. Review of aspirin and clopidogrel resistance in peripheral arterial disease. J Vasc Surg 2017; 66(5): 1576–1586. DOI: 10.1016/j.jvs.2017.07.065

15.

Allen

Barrett

Guo

, et al. Circulating monocyte-platelet aggregates are a robust marker of platelet activity in cardiovascular disease. Atherosclerosis 2019; 282: 11–18. DOI: 10.1016/j.atherosclerosis.2018.12.029

16.

Committee

. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348(9038): 1329–1339. DOI: 10.1016/s0140-6736(96)09457-3

17.

Spiliopoulos

Pastromas

Katsanos

, et al. Platelet responsiveness to clopidogrel treatment after peripheral endovascular procedures: the PRECLOP study: clinical impact and optimal cutoff value of on-treatment high platelet reactivity. J Am Coll Cardiol 2013; 61(24): 2428–2434. DOI: 10.1016/j.jacc.2013.03.036

18.

Kashyap

Schneider

Foteh

, et al. Early outcomes in the ROADSTER 2 study of transcarotid artery revascularization in patients with significant carotid artery disease. Stroke 2020; 51(9): 2620–2629. DOI: 10.1161/STROKEAHA.120.030550

19.

Berger

. Antithrombotic therapy in peripheral artery disease. Lancet 2018; 391(10117): 183–184. DOI: 10.1016/S0140-6736(17)32847-7

20.

Anand

Caron

Eikelboom

, et al. Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS Trial. J Am Coll Cardiol 2018; 71(20): 2306–2315. DOI: 10.1016/j.jacc.2018.03.008

21.

Bonaca

Nault

Giugliano

, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018; 137(4): 338–350. DOI: 10.1161/CIRCULATIONAHA.117.032235

22.

van Werkum

van der Stelt

Seesing

, et al. A head-to-head comparison between the VerifyNow P2Y12 assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective percutaneous coronary intervention. J Thromb Haemost 2006; 4(11): 2516–2518. DOI: 10.1111/j.1538-7836.2006.02187.x

23.

Levine

Bates

Bittl

, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: an update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016; 134(10): e123–e155. DOI: 10.1161/CIR.0000000000000404

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Response to clopidogrel in patients undergoing lower extremity revascularization